During a woman's reproductive life, a delicate and complex interplay of hormones are timed and controlled by the hypothalamus. The hormones that participate in the feedback system regulating the menstrual cycle include estrogens and progesterone, the pituitary gonadotropins FSH (follicle stimulating hormone) and LH (luteinizing hormone), and gonadotropin-releasing hormone (GnRH) from the hypothalamus.
Manipulation of the hormonal balance is a recognized approach of contraception and of treatment of benign gynecological disorders. In particular, administration of a GnRH compound for contraception has been described (U.S. Pat. Nos. 5,340,584; 5,211,952). Typically, the GnRH compound is administered in a slow or controlled-release fashion for continuous suppression of ovarian estrogen and progesterone production. Estrogen, often a progestin, and sometimes an androgen, are “added-back” to ameliorate the effects of hormonal deficiency. The hormone add-backs are also often administered in a slow, controlled-release or time-release fashion to maintain a constant hormonal serum level.
Treatment of benign gynecological disorders by administration of a GnRH compound has also been described (U.S. Pat. Nos. 5,340,584; 5,340,585; 5,681,817). During a women's reproductive years, defined as the time between onset of menses (menarche) and the final episode of bleeding (menopause), that is a premenopausal woman, a variety of benign gynecological disorders can occur. Common benign gynecological disorders include, but are not limited to, premenstrual syndrome, endometriosis, uterine leiomyomata (uterine fibroids), and polycystic ovarian syndrome. As for contraceptive use, a GnRH compound is administered to suppress ovarian follicle development and sex steroid production to relieve or treat symptoms associated with the disorder.
The administration of drugs by absorption through mucosae, such as the nasal mucosa or vaginal mucosa, has been of considerable interest in recent years. This route of drug delivery is an alternative to oral administration in cases where drugs are poorly absorbed or are extensively metabolized in the gastrointestinal tract or subjected to first-pass metabolism in the liver. In particular, nasal mucosa has the desirable properties of being highly vascular leading to rapid uptake and the avoidance of first-pass metabolism in the liver, since the venous system from the nose passes directly into the systemic circulatory system. The nasal mucosa also exhibits moderate permeability to water-soluble compounds, comparable to that of the ileum. The permeability of nasal mucosa is higher for most compounds than other mucosae, due in part to the difference in structure of the cells lining the body cavities.
Efficiency of delivery of drugs by an intra-nasal route is influenced by the degree and rapidity of enzymatic degradation, the nasal clearance rate, as well as the drug's permeability through the mucosa. The clearance rate is produced by the coordinated movement of cilia and is known to be highly dependent upon the prevailing physiological and pathological conditions. Thus, for many drugs administration intranasally is inefficient due to low uptake of the drug, hence low bio-availability.
Another potential problem associated with intranasal delivery is mucosal irritation. Irritation caused by the drug itself and/or by absorption or penetration promoters or enhancers often limits the success of nasal formulations. Chronic administration of irritating nasal formulations can cause necrosis, inflammation, exudation, removal of the epithelial monolayer or can lead to irreversible damage to the nasal mucosa.
Nasal formulations comprised of a GnRH compound have been described (see, for example, U.S. Pat. Nos. 5,116,817; 4,476,116). However, it is unknown if intranasal delivery of a composition containing multiple active agents, such as a GnRH compound and one or more hormonal agents, is suitable for contraception or for treatment of benign gynecological disorders. For example, it is unknown if the presence of multiple agents in the formulation interfere with absorption of one or another of the agents. Formulations comprised of a GnRH compound and one or more hormonal agents that are sufficiently non-irritating to the nasal mucosa for commercial viability have also not been described.